Gene Therapy for Neurologic Disease

Suhr, Steven T.; Gage, Fred H.

doi:10.1001/archneur.1993.00540110122012

Cited by 105 publications

(33 citation statements)

References 140 publications

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“…13,14,16,17,21,22,[36][37][38] Cationic liposome-mediated gene transfer is non-immunogenic and non-toxic at therapeutic doses. 33,39 This paper is the first systematic report using DC-Chol liposome-mediated neurotrophic gene transfer to treat neuronal injury in in vitro and in vivo models of CNS injury.…”

Section: Discussionmentioning

confidence: 99%

Liposome-mediated NGF gene transfection following neuronal injury: potential therapeutic applications

et al. 1999

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We have systematically investigated the therapeutic potenine acetyltransferase (ChAT) activity in cultures following tial of cationic liposome-mediated neurotrophic gene transcalcium-dependent depolarization injury. In in vivo studies, fer for treatment of CNS injury. Following determination of following intraventricular injections of NGF cDNA comoptimal transfection conditions, we examined the effects of plexed with DC-Chol liposomes, ELISA detected nine-to dimethylaminoethane-carbamoyl-cholesterol (DC-Chol) 12-fold increases of NGF in rat CSF. Further studies liposome-mediated NGF cDNA transfection in injured and showed that liposome/NGF cDNA complexes could attenuuninjured primary septo-hippocampal cell cultures and rat ate the loss of cholinergic neuronal immunostaining in the brains. In in vitro studies, we detected an increase of NGF rat septum after traumatic brain injury (TBI). Since deficits mRNA in cultures 1 day after transfection. Subsequent in cholinergic neurotransmission are a major consequence ELISA and PC12 cell biological assays confirmed that culof TBI, our studies demonstrate for the first time that DCtured cells secreted soluble active NGF into the media from Chol liposome-mediated NGF gene transfection may have day 2 after gene transfection. Further experiments showed therapeutic potential for treatment of brain injury. that such NGF gene transfection reduced the loss of chol-

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Section: Discussionmentioning

confidence: 99%

Liposome-mediated NGF gene transfection following neuronal injury: potential therapeutic applications

et al. 1999

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“…DSPE-PEG 2000-maleimide was custom synthesized by Shearwater Polymers. [␣- NaI and N-succinimidyl [2, H]propionate ( 3 H-NSP) was from Amersham Life Science. The nick translation system was purchased from GIBCO͞BRL.…”

Section: Methodsmentioning

confidence: 99%

“…T he expression of exogenously administered genes in brain has been achieved in vivo with either viral vectors or cationic liposomes (1)(2)(3)(4). However, in either case, highly invasive routes of administration were used, owing to the failure of gene medicines to cross the brain capillary wall, which forms the blood-brain barrier (BBB) in vivo.…”

mentioning

confidence: 99%

Noninvasive gene targeting to the brain

Shi

Pardridge

2000

Proc. Natl. Acad. Sci. U.S.A.

254

213

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Gene therapy of the brain is hindered by the presence of the blood-brain barrier (BBB), which prevents the brain uptake of bloodborne gene formulations. Exogenous genes have been expressed in the brain after invasive routes of administration, such as craniotomy or intracarotid arterial infusion of noxious agents causing BBB disruption. The present studies describe the expression of an exogenous gene in brain after noninvasive i.v. administration of a 6-to 7-kb expression plasmid encoding either luciferase or ␤-galactosidase packaged in the interior of neutral pegylated immunoliposomes. The latter are conjugated with the OX26 mAb to the rat transferrin receptor, which enables targeting of the plasmid DNA to the brain via the endogenous BBB transferrin receptor. Unlike cationic liposomes, this neutral liposome formulation is stable in blood and does not result in selective entrapment in the lung. Luciferase gene expression in the brain peaks at 48 h after a single i.v. administration of 10 g of plasmid DNA per adult rat, a dose that is 30-to 100-fold lower than that used for gene expression in rodents with cationic liposomes. ␤-Galactosidase histochemistry demonstrated gene expression throughout the central nervous system, including neurons, choroid plexus epithelium, and the brain microvasculature. In conclusion, widespread gene expression in the brain can be achieved by using a formulation that does not employ viruses or cationic liposomes, but instead uses endogenous receptor-mediated transport pathways at the BBB.blood-brain barrier ͉ transferrin receptor ͉ monoclonal antibody ͉ gene therapy

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“…Gene transfer into the central nervous system (CNS) as a possible route for gene therapy of neurological diseases, either by in vivo or ex vivo methods, has gained attention in recent years (see reviews [1][2][3][4] ). Among various gene delivery systems, viral vector-mediated gene transfer is considered to be the most efficient approach.…”

Section: Introductionmentioning

confidence: 99%

Gene transfer and expression in oligodendrocytes under the control of myelin basic protein transcriptional control region mediated by adeno-associated virus

et al. 1998

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In this study, a rAAV vector carrying a reporter gene,Infusion of approximately 6 × 10 9 particles (2 × 10 5 infec-'humanized' green fluorescent protein (GFP), linked to the tious units) of rAAV-MBP-GFP into mouse brains resulted transcriptional control region from the myelin basic protein in the GFP expression specifically in white matter. The (MBP) gene (a myelin-forming cell-specific gene) was con-GFP protein was detected 15 days later by immunostainstructed. Transduction of oligodendrocytes was carried out ing, specifically in the oligodendrocytes. No astrocytes both in vitro and in vivo. The GFP expression was detected were transduced. Our studies suggested that cell types for at least 3 weeks in both transduced oligodendrocyte cell other than neurons in the central nervous system can also line (MOCH-1 cells) and primary cultures of rat oligodendbe transduced by rAAV using a cell-type-specific transcriprocytes. Preferential GFP expression in oligodendrocytes tional control region or promoter. The MBP transcriptional was observed in the primary cultures. In contrast, transduccontrol region might be suitable for gene therapy and other tion with rAAV carrying the CMV promoter produced neurobiology studies requiring direct targeting to the myelistronger GFP fluorescence in various cell types, with the nating cells. majority of GFP-expressing cells being the astrocytes.

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Gene Therapy for Neurologic Disease

Cited by 105 publications

References 140 publications

Liposome-mediated NGF gene transfection following neuronal injury: potential therapeutic applications

Liposome-mediated NGF gene transfection following neuronal injury: potential therapeutic applications

Noninvasive gene targeting to the brain

Gene transfer and expression in oligodendrocytes under the control of myelin basic protein transcriptional control region mediated by adeno-associated virus

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